Italy is a leading country in the biogas sector. Energy crops and manure are converted into biogas using anaerobic digestion and, then, into electricity using internal combustion engines (ICEs). Therefore, there is an urgent need for improving the efficiency of these engines taking the real operation into account. To this purpose, in the present work, the organic Rankine cycle (ORC) technology is used to recover the waste heat contained in the exhaust gases of a 1 MWel biogas engine. The ICE behavior being affected by the biogas characteristics, the ORC unit is designed, firstly, using the ICE nameplate data and, then, with data measured during a one-year monitoring activity. The optimum fluid and the plant configuration are selected in both cases using an “in-house” optimization tool. The optimization goal is the maximization of the net electric power while the working fluid is selected among 115 pure fluids and their mixtures. Results show that a recuperative ORC designed using real data guarantees a 30% higher net electric power than the one designed with ICE nameplate conditions.